Neural crest rules the gut

The neurons and glial cells that regulate gut function derive from neural crest cells that emerge from the developing neural tube. Lasrado et al. used single-cell transcriptomics and mosaic mutagenesis to follow how the enteric nervous system is built in mice. Overlapping expression of regulatory programs supports dynamic determination of cell fates, with the developing neurons organized by clonal lineages. The clonal build model may explain how gut motility is coordinated in sequential segments and gut secretion is coordinated with motility.

Abstract

The enteric nervous system (ENS) is essential for digestive function and gut homeostasis. Here we show that the amorphous neuroglia networks of the mouse ENS are composed of overlapping clonal units founded by postmigratory neural crest–derived progenitors. The spatial configuration of ENS clones depends on proliferation-driven local interactions of ENS progenitors with lineally unrelated neuroectodermal cells, the ordered colonization of the serosa-mucosa axis by clonal descendants, and gut expansion. Single-cell transcriptomics and mutagenesis analysis delineated dynamic molecular states of ENS progenitors and identified RET as a regulator of neurogenic commitment. Clonally related enteric neurons exhibit synchronous activity in response to network stimulation. Thus, lineage relationships underpin the organization of the peripheral nervous system.